T helper subsets regulate inflammatory diseases, including the development of allergic lung inflammation associated with asthma. The development of T helper subsets in controlled by a network of transcription factors that promote the expression of cytokines and other genes associated with the ability of a T helper cell to promote disease. This proposal focuses on the most recently identified subset of T helper cells, Th9 cells that differentiate in response to TGF? and IL-4. Experiments in the proposal will define transcription factors that are important for Th9 cells to promote disease. In the previous funding period we determined a Th9 gene signature and a subset of genes that functionally contribute to the Th9 phenotype. We identified the ETS family member PU.1 as a transcription factor that promotes IL-9 production as it represses Th2 cytokine expression, and that PU.1 expression in T cells is important for the development of allergic inflammation. We defined PU.1 as downstream of the TGF? signal, and demonstrated that IRF4 and BATF are downstream of the IL-4/STAT6 signal. We characterized BATF as a factor important for Th9 development and for allergic inflammation. In the next funding period we will define the function of an ETS family member that might be a lineage-defining factor, and has unique function from PU.1. We will determine how these factors promote IL-9 expression, and also determine how they contribute to the pro-allergic phenotype of Th9 cells. We will further determine the mechanism for the ability of BATF to only promote IL-9 production in Th9 cells, and how BATF contributes to allergic inflammation in T helper cell subsets. Together, the proposed experiments will elucidate a network of transcription factors that regulate IL-9 production and promote a functionally pro-allergic T helper cell subset. Moreover, these studies will define novel contributions of T cells t allergic inflammation and potentially identify new targets for therapeutic intervention.
Allergic inflammation is responsible for a variety of atopic diseases including asthma. We are characterizing a type of T cell that regulates allergic disease. These studies will develop a new understanding of the mechanisms of disease and identify new targets for disease intervention.
| Koh, Byunghee; Abdul Qayum, Amina; Srivastava, Rajneesh et al. (2018) A conserved enhancer regulates Il9 expression in multiple lineages. Nat Commun 9:4803 |
| Imam, Tanbeena; Park, Sungtae; Kaplan, Mark H et al. (2018) Effector T Helper Cell Subsets in Inflammatory Bowel Diseases. Front Immunol 9:1212 |
| Ulrich, Benjamin J; Verdan, Felipe Fortino; McKenzie, Andrew N J et al. (2017) STAT3 Activation Impairs the Stability of Th9 Cells. J Immunol 198:2302-2309 |
| Ramadan, Abdulraouf; Griesenauer, Brad; Adom, Djamilatou et al. (2017) Specifically differentiated T cell subset promotes tumor immunity over fatal immunity. J Exp Med 214:3577-3596 |
| Kaplan, Mark H (2017) The transcription factor network in Th9 cells. Semin Immunopathol 39:11-20 |
| Rauber, Simon; Luber, Markus; Weber, Stefanie et al. (2017) Resolution of inflammation by interleukin-9-producing type 2 innate lymphoid cells. Nat Med 23:938-944 |
| Huang, Su; Shen, Yingjia; Pham, Duy et al. (2017) IRF4 Modulates CD8+ T Cell Sensitivity to IL-2 Family Cytokines. Immunohorizons 1:92-100 |
| Olson, Matthew R; Ulrich, Benjamin J; Hummel, Sarah A et al. (2017) Paracrine IL-2 Is Required for Optimal Type 2 Effector Cytokine Production. J Immunol 198:4352-4359 |
| Koh, Byunghee; Hufford, Matthew M; Sun, Xin et al. (2017) Etv5 Regulates IL-10 Production in Th Cells. J Immunol 198:2165-2171 |
| Koh, Byunghee; Hufford, Matthew M; Pham, Duy et al. (2016) The ETS Family Transcription Factors Etv5 and PU.1 Function in Parallel To Promote Th9 Cell Development. J Immunol 197:2465-72 |
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